NM_000194.3:c.22G>A

Variant names:

• chrX-134460333-G-A
• NM_000194.3:c.22G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_000194.3(HPRT1):​c.22G>A​(p.Val8Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V8G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

Genes affected

HPRT1 (HGNC:5157): (hypoxanthine phosphoribosyltransferase 1) The protein encoded by this gene is a transferase, which catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate. This enzyme plays a central role in the generation of purine nucleotides through the purine salvage pathway. Mutations in this gene result in Lesch-Nyhan syndrome or gout.[provided by RefSeq, Jun 2009]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a chain Hypoxanthine-guanine phosphoribosyltransferase (size 216) in uniprot entity HPRT_HUMAN there are 86 pathogenic changes around while only 1 benign (99%) in NM_000194.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.3178 (below the threshold of 3.09). GenCC associations: The gene is linked to Lesch-Nyhan syndrome, hypoxanthine guanine phosphoribosyltransferase partial deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2779046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3	c.22G>A	p.Val8Ile	missense_variant	Exon 1 of 9	ENST00000298556.8	NP_000185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8	c.22G>A	p.Val8Ile	missense_variant	Exon 1 of 9	1	NM_000194.3	ENSP00000298556.7
HPRT1	ENST00000462974.5	n.-18G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1011301 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 326263

African (AFR) AF: 0.00 AC: 0 AN: 21893

American (AMR) AF: 0.00 AC: 0 AN: 26539

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17340

East Asian (EAS) AF: 0.00 AC: 0 AN: 23587

South Asian (SAS) AF: 0.00 AC: 0 AN: 47905

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25445

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2964

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 803371

Other (OTH) AF: 0.00 AC: 0 AN: 42257

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lesch-Nyhan syndrome;C0268117:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency Uncertain:1

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with HPRT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 8 of the HPRT1 protein (p.Val8Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Benign	0.28	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	-0.37	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.25	N
REVEL	Uncertain	0.37
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.25		Loss of catalytic residue at V8 (P = 0.011);
MVP		0.72
MPC		1.3
ClinPred		0.36	T
GERP RS		3.1
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.81
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

hg19: chrX-133594363;